SAN FRANCISCO — Colorectal cancer (CRC) has increased dramatically in adults younger than 50 years of age in many high-income countries, and there has been speculation as to why. Now, a small study points to differences in the gut microbiome between younger and older CRC patients.
The study found that Fusobacterium nucleatum, for example, an oral bacterium that is indigenous to the human oral cavity and plays a role in periodontal disease, had a higher presence in younger patients than previously thought.
Another type of bacteria, Moraxella osloensis, was detected at a rate that was almost fourfold higher in patients older than 75 years than in those younger than 45 years.
These findings are very preliminary, but these are “interesting hypothesis-generating data,” said lead author Benjamin Weinberg, MD, assistant professor of medicine at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC.
“But we have a long way to go,” he stressed. “The hope is that it can lead us to a potential target that we use vaccines or antibiotics, which we can use to manipulate the microenvironment.”
The study results were presented here at the 2020 Gastrointestinal Cancers Symposium.
Weinberg noted that there has been a rise in colorectal cancer in younger adults, mostly in the last 20 years and with tumors that primarily occur on the left side and rectum. “We really don’t have a great explanation as to why,” he told Medscape Medical News.
“We’ve done a lot of studies looking at genetic mutations, to see if there are differences between younger and older patients. There are some subtle differences, especially if you compare the very young patients to the average colorectal cancer patients, but for the most part there aren’t any real genetic differences.”
Weinberg added that even though many younger patients have genetically related cancers, or Lynch syndrome, that still doesn’t account for the observed increased incidence.
The rising incidence of colorectal cancer among younger populations has spurred a discussion over whether or not to lower the recommended age to begin screening. The American Cancer Society now recommends that adults at average risk should begin screening at age 45 rather than 50. Conversely, the US Preventive Services Task Force (USPSTF) has maintained the starting age at 50.
Suggestions of Differences
In this study, Weinberg and colleagues compared the intratumoral microbiome in patients with colorectal cancer who were diagnosed before age 45 years and after age 65. Both primary and metastatic tumors were included in the analysis.
DNA was extracted from the tumors and analyzed using 16S ribosomal gene sequencing, and the frequency of F nuc and other types of bacterial and fungal DNA in tumors from younger and older patients.
“A robust DNA sequencing was done not for tumor genetics, but for bacterial and fungal DNA,” said Weinberg. “We got a snapshot of all the bacterial and fungi that are found. The technology we used is relatively new and a lot of these organisms can’t be grown in a culture — we are amassing quite a bit of data.”
He noted that this study is reporting on the first 31 patients that have been analyzed, but the hope is to increase that number to 140 patients. “We have seen F nuc in younger patients, particularly in the left side, when it’s been thought to be a bacterium seen in older patients with right-sided tumors,” he said.
The median age of younger patients was 39.2 years (n = 18) and 72.8 years
(n = 13) for the older patients. A total of 478 unique bacterial and fungal species were detected in the samples, with F nuc detected in tumors of 5 younger patients (28%, 4 left-sided and 1 right-sided primary) and 3 older patients (23%, 1 left-sided and 2 right-sided; P = NS, Fisher’s Exact test).
A significant difference was observed in the rate of M osloensis (11% vs. 46%,
P = .043, Fisher’s Exact test) between the younger and older patients. However, no significant difference was seen in the microbiome diversity in younger vs older patients (46 vs. 42 average species, P = NS).
Defining the microbiome has potential to identify younger individuals at risk for colorectal cancer. “There may be a role for adaptive screening, and so not everyone will need a colonoscopy,” said Weinberg. “If we can identify high risk stool microbiome — trying to look at the stool vs the tumor bacterial composition — it may help us identify someone at high risk of developing colorectal cancer.”
Preliminary but Interesting
Commenting on the study, Tong Dai, MD, PhD, associate professor, Division of GI Oncology, and associate director, Early Phase Clinical Trials Program, Roswell Park Cancer Center, Buffalo, New York, noted that there is a real need for research in this area, and credits the authors for undertaking this ambitious project.
“However, there are some serious limitations to this work,” said Dai, who was not involved with the research. “The study enrolled 64 younger and 64 older patients, but only 18 and 13 tumors, respectively, were analyzed. Also, the percentage of Fusobacterium nucleatum positive tumors was 28% vs. 23% — not a significant difference.”
“Given the very small sample analysis with negative results, it’s premature to draw a correlation between colorectal cancer incidence and gut microbiome, let alone talking about causation and effects on patient outcome,” Dai said.
Richard Schilsky, MD, chief medical officer and executive vice president of the American Society of Clinical Oncology, also weighed in on the data. “The main point of interest in this abstract is that it continues to put our focus on the potential role of the microbiome in causing cancer,” he told Medscape Medical News . “I’ve seen data presented that the composition of bacteria in the mouth may influence the development of oral cancers, and now they’re raising the question if there is a difference in the composition of the microbiome in younger vs older patients in colorectal cancer.”
He also pointed out that there is accumulating data about the association between the microbiome and the immune system, and response to immune checkpoint inhibitors. “The potential to influence physiology is huge, but how it does that is the question,” Schilsky said. “This abstract shows that there is a lot of diversity in the microbiome, so the question is: Is it the diversity, the predominance of one or more species, the number of organisms, the interaction between the organisms and the host? It’s probably all of those in some shape or form.”
“This particular abstract is still very preliminary and [has] very small numbers, but it raises an interesting hypothesis that we will continue to look at,” he added.
The study was supported by the Colorectal Cancer Alliance and the Victoria Casey and Peter Teeley Foundation. Weinberg has disclosed relationships with OncLive, Rafael Pharmaceuticals, Tempus, Bayer, Lilly, Taiho Pharmaceutical, AbbVie (Inst), Isofol Medical (Inst), Novartis (Inst), and Caris Life Sciences.
Gastrointestinal Cancers Symposium (GICS) 2020: Abstract 241. Presented January 25, 2020.